Effect of Solvent on the Crystal Structure and Habit of Hydrocortisone

The effect of different solvents including methanol, pyridine, acetone, dichloromethane, and isopropanol on the crystal structure or habit of hydrocortisone (HC) were studied using X-ray diffraction (XRD) or scanning electron microscopy. It was found that solvent had a significant impact on HC structure and morphology. The solvent molecules could enter the crystal lattice, forming HC solvates. Single crystals of HC were obtained from methanol, and its crystal structure and melting point were measured by XRD and differential scanning calorimetry (DSC), respectively. Only one endothermic thermal transition peak at 222.4 °C on the DSC curve of the HC crystal dried at 130.0 °C was found, while another additional endothermic peak at 106.5 °C can be observed when it was dried at room temperature. This additional peak was attributed to the desolvation of the solvent methanol. The formation of HC-pyridine solvate provided another proof confirming this phenomenon of solvent entering the crystal structure. The desolvation peak temperature of HC-pyridine was 122.6 °C, higher than the solvent’s boiling point, indicating that intensive interactions existed between the solvent and the HC molecules, which further led to a variety of solvate crystal structures. The crystal habit of HC also changed remarkably when it was crystallized from different solvents mentioned above, from platelet-like, bladelike, prism to parallelepiped morphology. In various instantaneous microenvironments, HC was found to grow into different habits depending on the solvent that entered the inner crystal lattice as well as the external crystallization conditions.